Controlled absorption diltiazem pharmaceutical formulation

ABSTRACT

A controlled absorption diltiazem pellet formulation for oral administration comprises a core having diltiazem or a pharmaceutically acceptable salt thereof as the active ingredient. The core is surrounded by a coating which has only a single layer which is comprised of a relatively major proportion of talc and relatively minor proportion of sodium lauryl sulfate admixed with a minor proportion of a pharmaceutically acceptable film-forming, first polymer permeable to water and diltiazem, and a major proportion of a pharmaceutically acceptable film-forming, second polymer that is less permeable to water and diltiazem than the first polymer. The core and the coating layer both exclude organic acids. The composition of the coating layer as well as the proportion of core to coating layer are effective to permit release of the diltiazem allowing controlled absorption following oral administration. By combining short lag and long lag pellets into a single formulation, the release of diltiazem is controlled over a twenty four hour period.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.08/369,100 filed Jan. 5, 1995, now abandoned.

FIELD OF THE INVENTION

The present invention relates to controlled absorption pharmaceuticalformulations and, in particular, to controlled absorption forms ofdiltiazem for once a day oral administration.

BACKGROUND OF THE INVENTION

Diltiazem, which is cis-(+)-3-(acetyloxy)-5-2-(dimethylamino)ethyl!-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, referred to herein as"diltiazem", is a benzothiazine derivative possessing calcium antagonistactivity. Diltiazem blocks the influx of calcium ions in smooth andcardiac muscle and thus exerts potent cardiovascular effects. Diltiazemhas been shown to be useful in alleviating symptoms of chronic heartdisease, particularly angina pectoris and myocardial ischemia andhypertension, while displaying a low incidence of side effects.Diltiazem is available as diltiazem hydrochloride in tablet form instrengths of 30, 60, 90 and 120 mg. and in capsule form in strengths of60, 90, 120, 180, 240 and 300 mg. Diltiazem is also available ininjectable form with a strength of 5 mg./ml.

Diltiazem therapy typically starts with 30 mg. administered 4 timesdaily. The dosage is gradually increased to 180 to 360 mg./day, given individed doses three or four times daily, at one- to two- day intervalsuntil an optimum response is obtained. Diltiazem is extensivelymetabolized by the liver. According to professional use informationissued by Marion Merrell Dow Inc., diltiazem in CARDIZEM® brand tabletsis absorbed to about 80% and is subject to an extensive first-passeffect, giving an absolute bioavailability, compared to intravenousadministration, of about 40%. Single oral doses of 30 to 120 mg. ofCARDIZEM® diltiazem tablets result in peak plasma levels two to threehours after administration. Detectable plasma levels occur within 30 to60 minutes after administration indicating that CARDIZEM® diltiazemtablets are readily absorbed. The plasma elimination half-life followingsingle or multiple administration is approximately 3.5 hours.Therapeutic blood levels of CARDIZEM® diltiazem tablets appear to be inthe range of 50 to 200 ng./ml.

Although conventional diltiazem tablets are administered three or fourtimes daily, such frequent drug administration may reduce patientcompliance and produce irregular blood levels. Consequently, adversetherapeutic effects can arise. There is therefore a need for a diltiazemformulation that ensures that diltiazem blood levels remain relativelystable over long periods of time without the need for frequent drugadministration.

U.S. Pat. Nos. 4,721,619, 4,891,230, 4,917,899 and 5,219,621 disclosediltiazem formulations that purport to require administration once everytwelve hours (i.e., twice a day). U.S. Pat. Nos. 4,894,240 and 5,002,776disclose diltiazem formulations that purport to require administrationonce every 24 hours (i.e., once a day). To obtain the dissolutionprofiles disclosed in these patents, the formulations disclosed requirea multi-layer membrane that coats the central core and an organic acidin the active core and/or in the multi-layer membrane. Suitable organicacids disclosed in these patents are adipic acid, ascorbic acid, citricacid, fumaric acid, malic acid, succinic acid and tartaric acid.According to professional use information issued by Marion Merrell DowInc., the CARDIZEM® CD diltiazem capsule is a sustained releasediltiazem capsule containing 120, 180, 240 or 300 mg. diltiazemhydrochloride with a suggested dosage of one capsule a day. Similarly,to obtain a 24-hour diltiazem release profile, the pellets in theCARDIZEM® CD diltiazem capsule include fumaric acid, an organic acid,and a multi-layer membrane that coats the central core. According to theaforementioned patents, the pellets must be dried for a number of hoursduring and after the coating process. This procedure increases themanufacturing cost of such pellets. Additionally, the organic acidincluded in such formulations may have an irritating effect.Accordingly, a need exists for a sustained release diltiazem formulationfor once a day administration which does not have an irritating effectand which also has a satisfactory dissolution rate.

SUMMARY OF THE INVENTION

The controlled absorption diltiazem pellet formulation for once a dayoral administration of the present invention comprises a mixture of longand short lag pellets, each having a core with diltiazem or apharmaceutically acceptable salt thereof as the active ingredient. Thecore is substantially free of an organic acid, i.e., the amount of suchorganic acid, if any, is sufficiently small so as not to substantiallyaffect the release rate of the drum from the core. The core and has acoating which has only a single layer which is comprised of a mixture ofa relatively large proportion of a lubricant and a relatively smallproportion of a wetting agent in admixture with a minor proportion of apharmaceutically acceptable film-forming, first polymer that ispermeable to water and diltiazem, and a major proportion of apharmaceutically acceptable film-forming, second polymer that is lesspermeable to water and diltiazem than the first polymer. As mentioned,the core and the coating layer of the pellets are substantially free oforganic acids. The composition of the coating layer is effective topermit release of the diltiazem allowing controlled absorption over atwenty four hour period following oral administration.

The core of the pellets is preferably comprised of a central sphere ofan inert ingredient, preferably a sugar sphere, diltiazem hydrochlorideand a pharmaceutical binder, preferably hydroxypropyl cellulose.

The film-forming polymers in the coating layer are preferably cationicpolymers synthesized from acrylic and methacrylic acid esters with a lowcontent of quaternary ammonium groups, known as EUDRAGIT RL and EUDRAGITRS. The wetting agent, preferably sodium lauryl sulfate, and thelubricant, preferably talc, as well as an optional plasticizing agent,preferably triethyl citrate, are also included in the coating layer.

By varying the proportion of the coating relative to the core, pelletswith different dissolution profiles are obtained. Thus, by using coresof the same size and by increasing the thickness of the coating, thedissolution profile changes, even though the compositions of the coreand the coating layer remain the same.

When measured in a type 2 dissolution apparatus (paddle) according tothe U.S. Pharmacopoeia XXII in 0.1N HCl at 100 r.p.m. and at 37° C., ashort lag pellet formulation exhibits the following dissolution profile:from 0% to 25% of the total diltiazem is released after 2 hours, from30% to 100% of the total diltiazem is released after 4 hours, from 60%to 100% of the total diltiazem is released after 6 hours, from 80% to100% of the total diltiazem is released after 8 hours, and from 90% to100% of the total diltiazem is released after 13 hours.

When measured in a type 2 dissolution apparatus (paddle) according tothe U.S. Pharmacopoeia XXII in 0.1N HCl at 100 r.p.m. and at 37° C., along lag pellet formulation exhibits the following dissolution profile:from 0% to 10% of the total diltiazem is released after 2 hours, from 0%to 10% of the total diltiazem is released after 4 hours, from 0% to 15%of the total diltiazem is released after 6 hours, from 0% to 15% of thetotal diltiazem is released after 8 hours, from 60% to 100% is releasedafter 18 hours and from 90% to 100% of the total diltiazem is releasedafter 24 hours.

By encapsulating a mixture of these two types of pellets, and measuringin a type 2 dissolution apparatus (paddle) in 0.1N HCl at 100 r.p.m. andat 37° C., a once a day controlled release diltiazem capsule formulationexhibits the following dissolution profile is obtained: from 0% to 30%of the total diltiazem is released after 2 hours, from 0% to 50% of thetotal diltiazem is released after 4 hours, from 20% to 60% of the totaldiltiazem is released after 6 hours, from 30% to 70% of the totaldiltiazem is released after 8 hours, from 30% to 100% of the totaldiltiazem is released after 13 hours, and from 80% to 100% of the totaldiltiazem is released after 24 hours.

When a preferred embodiment, having a long lag to short lag pellet ratioof 60:40, is measured in a type 2 dissolution apparatus (paddle) in 0.1NHCl at 100 r.p.m. and at 37° C., the following dissolution profile isobtained: not more than 10% of the total diltiazem is released after 1hour, from 20% to 45% of the total diltiazem is released after 6 hours,from 35% to 45% of the total diltiazem is released after 8 hours, from35% to 45% of the total diltiazem is released after 11 hours, not lessthan 85% of the total diltiazem is released after 18 hours, and not lessthan 90% of the total diltiazem is released after 24 hours.

The short lag pellet of this preferred embodiment will typically exhibitthe following in vitro dissolution profile: not more than 10% of thetotal diltiazem is released after 1 hour, 50% of the total diltiazem isreleased between 3 and 41/2 hours, and not less than 85% of the totaldiltiazem is released after 8 hours. The long lag pellet of thispreferred embodiment will typically exhibit the following in vitrodissolution profile: not more than 5% of the total diltiazem is releasedafter 1 hour, 50% of the total diltiazem is released between 12 and 16hours, and not less than 85% of the total diltiazem is released after 18hours.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of percent dissolution against timein hours for the short lag pellets, the long lag pellets, and the blendcontaining such short lag pellets and long lag pellets prepared inaccordance with Example 1, at pH 1.0;

FIG. 2 is a graphical representation of plasma levels (ng/ml) ofdiltiazem against time (hours) after administration to fasted humans forthe diltiazem capsule formulation prepared in Example 1 and for aCARDIZEM® CD diltiazem capsule;

FIG. 3 is a graphical representation of plasma levels (ng/ml) ofdiltiazem against time (hours) after administration to fed humans forthe diltiazem capsule formulation prepared in Example 1 and for aCARDIZEM® CD diltiazem capsule;

FIG. 4 is a graphical representation of percent dissolution against timein hours for the short lag pellets, the long lag pellets, and the blendcontaining such short lag pellets and long lag pellets prepared inaccordance with Example 1, at pH 7.01;

FIG. 5 is a graphical representation of percent dissolution against timein hours for the diltiazem capsule blend formulation prepared in Example1 and for CARDIZEM® CD capsules, in 0.1N HCl.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

The present invention provides a once a day diltiazem formulation fororal administration comprised of a tablet or capsule filled with pelletscontaining diltiazem. A mixture of two types of pellets is utilized, onein which the diltiazem is released into the bloodstream of a humansubject soon after administration and one in which the diltiazem isreleased after a delay of approximately over 6 hours. As a result, theamount of diltiazem in the human subject remains relatively constantafter onset over a 24 hour period after administration.

The pellets are comprised of a central core containing the activeingredient and a single coating layer covering the core.

The active core is preferably comprised of a central sphere, bead orseed of an inert ingredient, a pharmaceutically acceptable diltiazemcontaining compound and a pharmaceutical binder, emulsifier orstabilizer. The central inert core is preferably comprised of a sugar orstarch sphere having an average diameter of from about 0.5 mm. to about1.5 mm. The pharmaceutically acceptable diltiazem containing compound ispreferably in the form of a pharmaceutically acceptable salt thereof,more particularly the hydrochloride salt thereof, diltiazemhydrochloride. The pharmaceutical binder is preferably hydroxypropylcellulose, although other suitable known binders may be used, such as,for example, acacia, carboxymethylcellulose sodium, dextrin,ethylcellulose, gelatin, glucose, guar gum, hydroxyethyl cellulose,hydroxypropyl methylcellulose, methylcellulose, polymethacrylates,povidone, pregelatinized starch, sodium alginate, and zein, or a mixtureof any two or more of the foregoing binders. No organic acids, such asadipic acid, ascorbic acid, citric acid, fumaric acid, malic acid,succinic acid, tartaric acid and fumaric acid, are required to beincluded in the core. The core may also include further components tothose specified above such as a dispersing agent, glidant and/orsurfactant.

The single coating layer is preferably comprised of a mixture of arelatively large proportion of a lubricant and a relatively smallproportion of a wetting agent in admixture with a minor proportion of afirst polymer that is permeable to diltiazem and water and a majorproportion of a polymer that is less permeable to diltiazem and waterthan the first polymer. No organic acids, such as adipic acid, ascorbicacid, citric acid, fumaric acid, malic acid, succinic acid, tartaricacid and fumaric acid, are required to be included into the coatinglayer. A preferred permeable first polymer is the cationic polymersynthesized from acrylic and methacrylic acid ester with a low contentof quaternary ammonium groups, known as EUDRAGIT RL manufactured by RohmPharma GmbH. In this compound, the ammonium groups give rise to thepermeability of the polymer. The permeability of EUDRAGIT RL is reportedas independent of pH. A preferred less permeable second polymer isanother such cationic polymer known as EUDRAGIT RS manufactured by RohmPharma GmbH. EUDRAGIT RS is less permeable than EUDRAGIT RL becauseEUDRAGIT RS has fewer ammonium groups. The permeability of EUDRAGIT RSis reported to be also independent of pH.

Additional substances that can be used that are less permeable todiltiazem and water include ethylcellulose, cellulose acetate, cellulosepropionate (lower, medium or higher molecular weight), cellulose acetatepropionate, cellulose acetate butyrate, cellulose acetate phthalate,cellulose triacetate, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate),poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecylacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(propylene), poly(ethylene oxide), poly(ethyleneterephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate),poly(vinyl chloride) or polyurethane or a mixture of any two or more ofthese. Suitable naturally occurring polymers or resins that are lesspermeable to water and diltiazem include shellac, chitosan, gumjuniperor a mixture of two or more of these.

The single coating layer may alternatively be comprised of a mixture ofpolymers, synthetic and/or naturally occurring, that are freelypermeable, slightly permeable, water soluble, water insoluble, andpolymers whose permeability and/or solubility is affected by pH. Inaddition to those referred to above, such suitable polymers forinclusion into the coating layer include EUDRAGIT S, EUDRAGIT L,EUDRAGIT E, polyvinyl alcohol and polyvinylpyrrolidone. Commerciallyavailable polymeric solutions and/or suspensions may also be used. Thesesolutions/suspensions may optionally contain plasticizing agents toimprove the polymer characteristics of the coating. Examples of suchsolutions and/or suspensions include EUDRAGIT RL 30D, EUDRAGIT L 30D,EUDRAGIT E 12.5, EUDRAGIT RL 12.5 P, EUDRAGIT RS 12.5, AQUACOAT made byFMC Corporation, and SURE-LEASE made by Colorcon Inc. AQUACOAT is anaqueous polymeric dispersion of ethylcellulose and contains sodiumlauryl sulfate and cetyl alcohol. SURELEASE is an aqueous polymericdispersion of ethylcellulose and contains dibutyl sebacate, oleic acid,ammoniated water and fumed silica.

In addition to the polymers, the coating layer includes a lubricant anda wetting agent. Preferably the lubricant is talc and the wetting agentis sodium lauryl sulfate.

Suitable alternatives for sodium lauryl sulfate may include agents suchas acacia, benzalkonium chloride, cetomacrogol emulsifying wax,cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine,docusate sodium, sodium stearate, emulsifying wax, glycerylmonostearate, hydroxypropyl cellulose, lanolin alcohols, lecithin,mineral oil, monoethanolamine, poloxamer, polyoxyethylene alkyl ethers,polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene stearates, propylene glycol alginate,sorbitan esters, stearyl alcohol and triethanolamine, or a mixture ofany two or more of the foregoing.

Suitable alternatives for talc that may be included in the coating arecalcium stearate, colloidal silicon dioxide, glycerin, magnesiumstearate, mineral oil, polyethylene glycol, and zinc stearate, aluminumstearate or a mixture of any two or more of the foregoing.

A plasticizing agent is preferably included in the coating to improvethe elasticity and the stability of the polymer film and to preventchanges in the polymer permeability over prolonged storage. Such changescould affect the drug release rate. Suitable conventional plasticizingagents include acetylated monoglycerides, acetyltributylcitrate,acetyltriethyl citrate, castor oil, citric acid esters, dibutylphthalate, dibutylsebacate, diethyloxalate, diethyl malate,diethylfumarate, diethylphthalate, diethylsuccinate, diethylmalonate,diethyltartarate, dimethylphthalate, glycerin, glycerol, glyceryltriacetate, glyceryltributyrate, mineral oil and lanolin alcohols,petrolatum and lanolin alcohols, phthalic acid esters, polyethyleneglycols, propylene glycol, rape oil, sesame oil, triacetin, tributylcitrate, triethyl citrate, and triethyl acetyl citrate, or a mixture ofany two or more of the foregoing. Triethyl citrate is the presentlypreferred plasticizing agent.

To the extent that naturally occurring oils and/or waxes can be used aspart of the core and/or coating, these oils and waxes are substantiallyfree of organic acids, i.e., the amount of such organic acid, if any, issufficiently small so as not to substantially affect the release rate ofthe drug from the core.

Typically the core of the pellet comprises 60 to 80% of diltiazemhydrochloride as the active ingredient, 2 to 6% of hydroxypropylcellulose and 18 to 34% of sugar, expressed as percentages of the totalweight of the core. The coating layer of the pellet comprises 2 to 7% ofa polymer of acrylic and methacrylic acid esters as the first polymer,53 to 59% of a polymer of acrylic and methacrylic acid esters as thesecond polymer, 0 to 8 % of triethyl citrate, 0 to 8% of sodium laurylsulfate, and 31 to 35% of talc, expressed as percentages of the totalweight of the coating layer.

By varying the proportion of the coating in each pellet relative to thecore, pellets with different dissolution profiles are obtained. Thus, bymaintaining the size of the core and by decreasing or increasing thethickness of the coating, the dissolution profile of the resultingpellet is varied, even though the compositions of the core and thecoating layer remain the same.

To form the active core, any suitable apparatus can be used and includea rotor granulator, pan coater, spheronizer and extruder. Preferably toform the active core, a slurry is made which includes ethanol, diltiazemand the binder. The slurry is then coated onto the central inert coresand the resultant active cores are then dried for about 1/4 to about 2hours at a temperature of from about 40° C. to about 60° C., preferablyfor about 1/2 hour at about 60° C.

To coat the active core, all of the coating ingredients except thelubricant are first dissolved in an ethanol solvent. The lubricant isthen added to and/or suspended in the solution. The single coating layeris applied to the active cores using a WURSTER bottom spray coater untilthe desired coating thickness is obtained. The coated active cores, orpellets, are then dried for about 1/4 to about 2 hours at a temperatureof from about 30° C. to about 60° C., preferably for about 1/2 hour at40° C., allowed to cool to ambient temperature, sieved through anappropriately sized mesh and dusted with talc.

Alternatively, the coating can be applied to the active cores using aconventional coating pan, an automated system such as a CF granulator,for example a FREUND CF granulator, a GLATT fluidized bed processor, anAEROMATIC, a modified ACCELA-COTA or any other suitably automated beadcoating equipment.

The pellets may be filled into hard or soft gelatin capsules. Thepellets may also be compressed into tablets using a binder and/orhardening agent commonly employed in tabletting such as microcrystallinecellulose sold under the trademark AVICEL or a co-crystallized powder ofhighly modified dextrins (3% by weight) and sucrose sold under thetrademark DI-PAC in such a way that the specific dissolution rate of thepellets is maintained.

EXAMPLE 1

Short Lag Pellets:

Diltiazem hydrochloride (10.050 kg.) and hydroxypropyl cellulose (0.625kg.) were mixed with ethanol (16.250 l) to form a homogeneous slurry.Sugar spheres (0.50 to 0.60 mm. in diameter) (5.000 kg.) were added intothe rotor granulator and the slurry then applied. After approximately 2hours, the active cores were dried for 1/2 hour at a temperature of 50°C.

To form the coating solution, EUDRAGIT RS (3.1 kg.), EUDRAGIT RL (0.22kg.), triethyl citrate (0.33 kg.) and sodium lauryl sulfate (0.075 kg.)were dissolved in ethanol (24.4 l). Talc (1.86 kg.) was then added tothe solution.

The single coating layer was applied to the active cores using a WURSTERbottom spray coater until an actual coat weight of about 12% based onthe total pellet weight was obtained. The coated active cores were driedfor about 1/2 hour at a temperature of about 40°, then cooled to ambienttemperature, sieved through a 1400 μm mesh and dusted with talc.

The resulting short lag pellets had the following composition:

    ______________________________________                                                         Short Lag Pellets                                            Ingredient       (per 100 g) Weight %                                         ______________________________________                                        Core:                                                                         diltiazem HCl     56.3 g     64.1%                                            hydroxypropyl cellulose                                                                         3.5 g      4.0                                              sugar spheres     28.0 g     31.9                                             Total             87.8 g     100.0%                                           Coating:                                                                      EUDRAGIT RL       0.5 g      4.1%                                             EUDRAGIT RS       6.8 g      55.3                                             triethyl citrate  0.7 g      5.7                                              sodium lauryl sulfate                                                                           0.2 g      1.6                                              talc              4.1 g      33.3                                             Total             12.3 g     100.0%                                           TOTAL (core + coating)                                                                         100.1 g                                                      ______________________________________                                    

Long Lag Pellets:

Diltiazem hydrochloride (10.050 kg.) and hydroxypropyl cellulose (0.625kg.) were mixed with ethanol (16.250 l.) to form a homogeneous slurry.Sugar spheres (0.50 to 0.60 mm. in diameter) (5.000 kg.) were added intothe rotor granulator and the slurry then applied. After approximately 2hours, the active cores were removed and dried for 1/2 hour at atemperature of 50° C.

To form the coating solution, EUDRAGIT RS (11.4 kg.), EUDRAGIT RL (0.81kg.), triethyl citrate (1.20 kg.) and sodium lauryl sulfate (0.275 kg.)were dissolved in ethanol (89.8 l.). Talc (6.82 kg.) was then added tothe solution.

The single coating layer was applied to the active cores using a WURSTERbottom spray coater until an actual coat weight of about 29% based ontotal pellet weight was obtained. The coated active cores were dried forabout 1/2 hour at a temperature of about 40° C., then cooled to ambienttemperature, sieved through a 1400 μm mesh and dusted with talc.

The resulting long lag pellets had the following composition:

    ______________________________________                                                         Long Lag Pellets                                             Ingredient       (per 100 g) Weight %                                         ______________________________________                                        Core:                                                                         diltiazem HCl     44.7 g     64.1%                                            hydroxypropyl cellulose                                                                         2.8 g      4.0                                              sugar spheres     22.2 g     31.9                                             Total             69.7 g     100.0%                                           Coating:                                                                      EUDRAGIT RL       1.2 g      4.0%                                             EUDRAGIT RS       16.8 g     55.4                                             triethyl citrate  1.8 g      5.9                                              sodium lauryl sulfate                                                                           0.4 g      1.3                                              talc              10.1 g     33.3                                             Total             30.3 g     99.9%                                            TOTAL (core + coating)                                                                         100.0 g                                                      ______________________________________                                    

Dissolution Test (pH 1.0) (pellets):

After the finished short lag and long lag pellets were dried toevaporate all solvents, the pellets were then subjected to a dissolutiontest. The dissolution rate of the pellets, 300 mg. diltiazem equivalent,was determined in a type 2 dissolution apparatus (paddle) according tothe U.S. Pharmacopoeia XXII in 0.1N HCl at 100 r.p.m. in 900 ml. at 37°C. The diltiazem hydrochloride was quantitatively determined using U.V.spectrophotometry at 238 nm. The dissolution test was performed sixtimes and the mean dissolution rate was as shown in FIG. 1 and below inTable 1:

                  TABLE 1                                                         ______________________________________                                                 Short Lag Pellets                                                                            Long Lag Pellets                                               (Mean % Diltiazem HCl                                                                        (Mean % Diltiazem HCl                                 Time (hours)                                                                           Released)      Released)                                             ______________________________________                                         1       3.2            0.3                                                    2       8.5            0.4                                                    3       18.9           --                                                     4       39.6           0.5                                                    5       68.2           --                                                     6       86.3           0.7                                                    7       92.4           --                                                     8       94.7           0.9                                                   10       96.7           1.3                                                   12       97.8           3.1                                                   14       --             14.5                                                  16       --             51.0                                                  18       --             86.5                                                  21       --             99.2                                                  24       --             100.3                                                 ______________________________________                                    

By comparing the composition of the short lag pellets with that of thelong lag pellets, it can be seen that the cores of the short lag pelletsand the long lag pellets have the same relative proportions ofingredients. Similarly, the coating layers of the two types of pelletshave the same relative proportions of ingredients. To generate differentdissolution profiles, the proportion per pellet of the coating relativeto the proportion of the core was changed. As can be seen from the datain Table 1, by maintaining the size of the core and by decreasing thethickness of the coating, a faster dissolution profile is obtained.

Dissolution Test (pH 1.0) (blend):

A mixture of the pellets described above was made comprising 40% shortlag pellets and 60% long lag pellets (by drug weight content). A 300 mg.diltiazem equivalent of the mixture was subjected to a dissolution test.The dissolution rate of the capsule formulation was determined in a type2 dissolution apparatus (paddle) according to the U.S. PharmacopoeiaXXII in 0.1N HCl at 100 r.p.m. in 900 ml. at 37° C. The diltiazemhydrochloride was quantitatively determined using U.V. spectrophotometryat 238 nm. The dissolution test was performed six times and the meandissolution rate was as shown in FIG. 1 and below in Table 2:

                  TABLE 2                                                         ______________________________________                                                   Blend Formulation                                                  Time (hours)                                                                             (mean % diltiazem HCl released)                                    ______________________________________                                         1         1.3                                                                 2         2.9                                                                 4         18.1                                                                6         36.2                                                                8         38.7                                                               10         39.7                                                               12         41.5                                                               14         51.4                                                               16         76.3                                                               18         95.1                                                               20         100.4                                                              ______________________________________                                    

Dissolution Test (pH 7.0) (pellets):

After the finished short and long lag pellets were dried to evaporateall solvents, the pellets were then subjected to a dissolution test. Thedissolution rate of the pellets, 300 mg diltiazem equivalent, wasdetermined in a type 2 dissolution apparatus (paddle) according to theU.S. Pharmacopoeia XXII at pH 7.0 using a phosphate buffer at 100 r.p.m.in 900 ml. at 37° C. The diltiazem hydrochloride was quantitativelydetermined using U.V. spectrophotometry at 238 nm. The dissolution testwas performed three times and the mean dissolution rate was as shown inFIG. 4 and below in Table 3.

                  TABLE 3                                                         ______________________________________                                                Short Lag Pellets                                                                              Long Lag Pellets                                             (mean % diltiazem HCl                                                                          (mean % diltiazem HCl                                Time (hours)                                                                          Released)        Released)                                            ______________________________________                                         1      4.9               1.4                                                  2      11.8              1.4                                                  4      61.7              1.5                                                  6      85.6              1.5                                                  8      87.4              2.9                                                 10      88.2             13.7                                                 12      89.0             46.4                                                 14      89.6             66.1                                                 16      90.4             70.5                                                 18      90.9             71.5                                                 21      92.0             72.1 (20 hrs)                                        24      92.7             72.6 (22 hrs)                                        ______________________________________                                    

Dissolution Test (pH 7.0) (blend)

A mixture of the pellets described above was made comprising 40% shortlag pellets and 60% long lag pellets (by drug content weight). A 300 mg.diltiazem equivalent of the mixture was subjected to a dissolution test.The dissolution rate of the capsule formulation was determined in a type2 dissolution apparatus (paddle) according to the U.S. PharmacopoeiaXXII at pH 7.0 using a phosphate buffer at 100 r.p.m. in 900 ml. at 37°C. The diltiazem hydrochloride was quantitatively determined using U.V.spectrophotometry at 238 nm. The dissolution test was performed threetimes and the mean dissolution rate was as shown in FIG. 4 and below inTable 4.

                  TABLE 4                                                         ______________________________________                                                   Blend Formulation                                                  Time (hours)                                                                             (mean % diltiazem HCl released)                                    ______________________________________                                         1         1.4                                                                 2         3.9                                                                 4         21.4                                                                6         31.7                                                                8         33.4                                                               10         39.5                                                               12         60.3                                                               14         77.4                                                               16         82.4                                                               18         83.2                                                               21         84.2                                                               24         85.4                                                               ______________________________________                                    

Comparative Dissolution Study

A mixture of the pellets described above was made comprising 40% shortlag pellets and 60% long lag pellets (by drug content weight). A 300 mgdiltiazem equivalent of the encapsulated mixture was subjected to adissolution test and compared to the reference product, CARDIZEM® CD,under the following conditions: apparatus 2 (paddle), 0.1N HCl, 100r.p.m., 900 ml, 37° C. The diltiazem hydrochloride was quantitativelydetermined using U.V. spectrophotometry at 238 nm. The dissolution testwas performed on 12 units (whole capsules) of both the test andreference product and the mean dissolution rate was as shown in FIG. 5and below in Table 5.

                  TABLE 5                                                         ______________________________________                                               Diltiazem HCl ER CARDIZEM ® CD Capsules,                           Time   Capsules, 300 mg 300 mg                                                (hours)                                                                              (mean % diltiazem released)                                                                    (mean % diltiazem released)                           ______________________________________                                         1     0.7              0.4                                                    6     37.0             32.2                                                   8     39.5             37.8                                                  11     40.9             39.5                                                  18     98.2             47.7                                                  24     100.7            89.2                                                  ______________________________________                                    

Pharmacokinetic Data:

Two, two-way, single dose crossover studies were performedsimultaneously to assess the bioequivalence of the diltiazem capsuleformulation (containing both short and long lag pellets) described abovein Example 1 and CARDIZEM® CD diltiazem capsules when given under fastedand fed conditions. The effects of the Example 1 capsule formulation(40% short lag pellets and 60% long lag pellets) and the CARDIZEM® CDdiltiazem capsule, each containing 300 mg. of diltiazem, were comparedin 20 human healthy male subjects after an overnight fast, and in 8subjects after a standard breakfast. Serial blood samples were collectedfrom the subjects over 48 hours after each 300 mg. dose. A two-weekwashout separated the dosings. Nineteen of the fasted subjects and sevenof the fed subjects completed the studies. Plasma samples from all ofthe subjects who completed the studies were analyzed using a validatedchromatograph procedure and are shown in FIG. 2 (fasted subjects) and inFIG. 3 (fed subjects). In FIGS. 2 and 3, the curves denoted as "Capsule"refer to the diltiazem capsule formulation described in Example 1 above.The pharmacokinetic data for the subjects (n=19) who fasted prior toadministration was as shown below in Table 5:

                  TABLE 5                                                         ______________________________________                                        Parameter   Example 1 Diltiazem                                                                         CARDIZEM ® CD                                   (fasted subjects)                                                                         Capsule Formulation                                                                         Capsule Formulation                                 ______________________________________                                        AUC.sub.0-48 (ng-hr/ml)                                                                   2783.29       2899.47                                             AUC.sub.inf (ng-hr/ml)                                                                    2872.76       2974.07                                             C.sub.max1 (ng/ml)                                                                        113.98        131.77                                              C.sub.max2 (ng/ml)                                                                        138.42        140.62                                              C.sub.max (ng/ml)                                                                         139.43        147.01                                              T.sub.max1 (hr)                                                                           6.56          5.32                                                T.sub.max2 (hr)                                                                           17.24         16.33                                               T.sub.max (hr)                                                                            15.80         10.99                                               K.sub.e (1/hr)                                                                            0.1319        0.1434                                              Elim.sub.1/2 (hr)                                                                         5.47          5.20                                                ______________________________________                                    

The pharmacokinetic data for the subjects (n=7) who were fed prior toadministration was as shown below in Table 6:

                  TABLE 6                                                         ______________________________________                                        Parameter   Example 1 Diltiazem                                                                         CARDIZEM ® CD                                   (fasted subjects)                                                                         Capsule Formulation                                                                         Capsule Formulation                                 ______________________________________                                        AUC.sub.0-48 (ng-hr/ml)                                                                   3146.01       3040.75                                             AUC.sub.inf (ng-hr/ml)                                                                    3217.37       3109.78                                             C.sub.max1 (ng/ml)                                                                        108.86        114.13                                              C.sub.max2 (ng/ml)                                                                        157.49        147.39                                              C.sub.max (ng/ml)                                                                         157.49        151.57                                              T.sub.max1 (hr)                                                                           6.67          7.04                                                T.sub.max2 (hr)                                                                           18.79         20.13                                               T.sub.max (hr)                                                                            18.79         17.63                                               K.sub.e (1/hr)                                                                            0.1394        0.1336                                              Elim.sub.1/2 (hr)                                                                         5.01          5.47                                                ______________________________________                                    

As can be seen from FIGS. 2 and 3, for both the Example 1 diltiazemcapsule formulation and for the CARDIZEM® CD capsule formulation, thereare two peak concentrations, C_(max1) and C_(max2), which occur at timesT_(max1) and T_(max2), respectively. The value for C_(max) refers to theleast square means of the overall peak concentration and the value forT_(max) refers to the least square means of the time to reach themaximum concentration. The K_(e) values are the apparent first orderelimination rate constants which relate to the rate at which the drug ismetabolized or excreted. The value for Elim_(1/2) calculated as 0.693/Kindicates the time required to reduce the concentration by 50%.

It will be observed that the pharmacokinetic data for the Example 1diltiazem capsule formulation and for the CARDIZEM® CD capsuleformulation are very similar even though the Example 1 diltiazem capsuleformulation does not employ an organic acid or a multi-layer coating.

Thus, while there have been shown and described and pointed outfundamental novel features of the invention as applied to a preferredembodiment thereof, it will be understood that various omissions andsubstitutions and changes in the form and details of the disclosedinvention, may be made by those skilled in the art without departingfrom the spirit of the invention. It is the intention, therefore, to belimited only as indicated by the scope of the claims appended hereto.

What is claimed is:
 1. A once-a-day controlled absorption diltiazempellet formulation for oral administration comprising a blend of longlag and short lag pellets, each of said pellets comprising:(a) a corecomprising 18% to 34% sugar spheres, 60% to 80% diltiazem hydrochlorideand 2% to 6% hydroxypropylcellulose, expressed as percentages of thetotal weight of the core, said core being substantially free of organicacid, the amount of any such organic acid being sufficiently small so asnot to substantially affect the release rate of diltiazem hydrochloridefrom the core, and (b) a single coating layer having a thicknesssurrounding said core, each coating layer consisting essentially of 31%to 35% talc, not more than 8% sodium lauryl sulfate, not more than 8%triethyl citrate, 2% to 7% of a first copolymer of acrylic andmethacrylic acid esters, and 53% to 59% of a second copolymer of acrylicand methacrylic acid esters, expressed as percentages of the totalweight of the coating layer, the first copolymer being permeable towater and diltiazem, the second copolymer being less permeable to waterand diltiazem than said first copolymer, the thickness of the coatinglayer surrounding the long lag pellet core being greater than thethickness of the coating layer surrounding the short lag pellet coresuch that the diltiazem from the core of the short lag pellets isreleased before the diltiazem from the core of the long lag pellets, thethicknesses of said coating layers of said short and long lag pelletsbeing effective to permit the release of a therapeutically effectiveamount of said diltiazem from said pellet formulation at a rate allowingcontrolled absorption thereof over, on the average, a twenty-four hourperiod following oral administration, said rate being measured in vitroas a dissolution rate of said pellets, which when measured in a type 2dissolution apparatus (paddle) according to the U.S. Pharmacopoeia XXIIin 0.1N HCl at 100 rpm substantially corresponds to the followingdissolution pattern:a) not more that 10% of the total diltiazem isreleased after 1 hour of measurement in said apparatus; b) from 20% to45% of the total diltiazem is released after 6 hours of measurement insaid apparatus; c) from 35% to 45% of the total diltiazem is releasedafter 8 hours of measurement in said apparatus; d) from 35% to 45% ofthe total diltiazem is released after 11 hours of measurement in saidapparatus; e) not less than 85% of the total diltiazem is released after18 hours of measurement in said apparatus; and f) not less than 90% ofthe total diltiazem is released after 24 hours of measurement in saidapparatus.
 2. The diltiazem pellet formulation of claim 1, wherein saidshort lag pellets, when measured in a type 2 dissolution apparatus(paddle) according to the U.S. Pharmacopoeia XXII in 0.1N HCl at 100rpm, exhibit the following in vitro dissolution profile: not more than10% of the total diltiazem is released after 1 hour, 50% of the totaldiltiazem is released between 3 and 41/2 hours, and not less than 85 %of the total diltiazem is released after 8 hours; and said long lagpellets, when measured in a type 2 dissolution apparatus (paddle)according to the U.S. Pharmacopoeia XXIII in 0.1N HCl at 100 rpm,exhibit the following in vitro dissolution profile: not more than 5% ofthe total diltiazem is released after 1 hour, 50% of the total diltiazemis released between 12 and 16 hours, and not less than 85 % of the totaldiltiazem is released after 18 hours.
 3. The pellet formulation of claim1, wherein the core further comprises at least one of a dispersingagent, a glidant and a surfactant.
 4. The pellet formulation of claim 2,wherein the core further comprises at least one of a dispersing agent, aglidant and a surfactant.
 5. A capsule or tablet formulation comprisingpellets according to claim
 1. 6. A capsule or tablet formulationcomprising pellets according to claim 2.